Download Metabolite Markers

The Great Plains Laboratory, Inc.
The following pages list the 74 metabolite markers of the Organic Acids Test. Included is the name of the metabolic marker, its clinical
significance, and usual initial treatment.
INTESTINAL MICROBIAL OVERGROWTH
Yeast and Fungal Markers
Citramalic Acid
Elevated citramalic acid is produced mainly by Saccharomyces species or Propionibacteria overgrowth.
High-potency, multi-strain probiotics may help rebalance GI flora.
5-Hydroxy-methyl-furoic Acid
A metabolite produced by Aspergillus and possibly other fungal species in the GI tract. Prescription or
natural antifungals, along with high-potency, multi-strain probiotics, may reduce overgrowth levels.
3-Oxoglutaric Acid
Indicates a possible yeast overgrowth in the GI tract. High-potency, multi-strain probiotics may help
rebalance GI flora.
Furan-2,5-dicarboxylic Acid
A metabolite produced by Aspergillus and possibly other fungal species in the GI tract. Prescription or
natural antifungals, along with high-potency, multi-strain probiotics, may reduce overgrowth levels.
Furancarbonylglycine
A metabolite produced by Aspergillus and possibly other fungal species in the GI tract. Prescription or
natural antifungals, along with high-potency, multi-strain probiotics, may reduce overgrowth.
Tartaric Acid
Produced by action of Candida hyaluronidase on the intercellular cement, hyaluronic acid. Oxidation of
the hyaluronic acid breakdown by white blood cell hypochlorite produces tartaric acid and arabinose.
Antifungal treatment and high-potency, multi-strain probiotics may help rebalance GI flora.
Arabinose
Produced by action of Candida hyaluronidase on the intercellular cement, hyaluronic acid. Oxidation of
the hyaluronic acid breakdown by white blood cell hypochlorite produces tartaric acid and arabinose.
Antifungal treatment and high-potency, multi-strain probiotics may help rebalance GI flora.
Carboxycitric Acid
Elevated yeast/fungal metabolites indicate overgrowth in the GI tract. Prescription or natural
antifungals, along with high-potency, multi-strain probiotics, may reduce overgrowth.
Tricarballylic Acid
A chemical byproduct released from fumonisins during passage through the gastrointestinal tract.
Fumonisins are fungal toxins produced primarily by F. verticillioides. Elevated levels can be caused by
the intake of corn or corn-based food contaminated with fumonisins.
Bacterial Markers
Hippuric Acid
A bacterial product of phenylalanine metabolism. Most hippuric acid in urine is derived from microbial
breakdown of chlorogenic acid, a common substance found in beverages and in many fruits and
vegetables. Higher levels indicate GI bacterial overgrowth that can be reduced with natural antibacterial agents and/or high-potency, multi-strain probiotics.
2-Hydroxyphenylacetic Acid
Elevated 2-hydroxyphenylacetic acid is associated with intestinal bacteria overgrowth. High-potency,
multi-strain probiotics may help rebalance GI flora.
4-Hydroxybenzoic Acid
A marker for intestinal dysbiosis. Results may also show elevated values as a result of ingestion of
foods such as jams and pie fillings containing paraben preservatives. The use of probiotics and the
exclusion of paraben-containing foods is the first treatment consideration.
4-Hydroxyhippuric Acid
A glycine conjugate of 4-hydroxybenzoic acid, a metabolite of paraben preservatives. May be elevated
after exposure to paraben antimicrobials in certain foods and cosmetics. Intake of fruits containing
polyphenols rich in anthocyanins, flavonols, and hydroxycinnamates may increase this compound in
the urine. Avoid exposure to parabens.
DHPPA in urine indicates intake of chlorogenic acid, a common substance in beverages and many fruits
and vegetables. Harmless or beneficial bacteria such as Lactobacilli, Bifidobacteria,
Bifidobacteria, and E. coli increase
DHPPA
(dihydroxyphenylpropionic acid) the breakdown of chlorogenic acid to DHPPA, so high values are mainly associated with increased
amounts of these species in the GI tract.
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Clostridia Bacterial Markers
4-Hydroxyphenylacetic Acid
A tyrosine metabolic product of certain Clostridia bacteria. Elevated levels are associated with
Clostridia overgrowth, small intestinal bowel overgrowth (SIBO), or small bowel disease. May also
indicate celiac disease.
HPHPA (3-(3-hydroxyphenyl)-3hydroxypropionic acid)
An elevated value indicates an overgrowth of certain Clostridia bacteria in the GI tract including
C. sporogenes, C. caloritolerans, and C. botulinum. This metabolite is commonly elevated in autism,
psychiatric disorders, and GI disorders. This metabolite inhibits the enzyme dopamine-betahydroxylase, leading to a derangement of neurotransmitter balance.
4-Cresol
An elevated value indicates an overgrowth in the GI tract of C. difficile. This metabolite is commonly
elevated in autism, psychiatric disorders, and GI disorders. This metabolite inhibits the enzyme,
dopamine-beta-hydroxylase, leading to a derangement of neurotransmitter balance.
3-Indoleacetic Acid
3-Indoleacetic acid is a tryptophan byproduct of the following Clostridia species: C. stricklandii, C.
lituseburense, C. subterminale, and C. putrefaciens. Very high amounts of this metabolite derived from
tryptophan may indicate a depletion of tryptophan needed for other physiological functions.
OXALATE METABOLITES
Glyceric Acid
Elevated in genetic hyperoxaluria type II. Normal values of glyceric acid rule out genetic causes of
significant elevation of oxalic acid in urine.
Glycolic Acid
Very elevated in genetic hyperoxaluria type I. Normal values of glycolic acid rule out genetic causes of
significant elevation of oxalic acid in urine. This genetic disease can be confirmed by DNA testing at the
Mayo Clinic. Glycolic Acid is high in fruits and vegetables.
Oxalic Acid
Elevated oxalic acid may be associated with dysbiosis from Aspergillus, Penicillium, and possibly
Candida, or from high doses of vitamin C. If yeast or fungal markers are elevated, antifungal therapy
may reduce oxalates. Elevated oxalic acid may also result from anti-freeze (ethylene glycol) poisoning.
Oxalic Acid may also be due to genetic mutations or SNPs in the oxalate pathway.
GLYCOLYTIC CYCLE METABOLITES
Lactic Acid
Elevated by a number of nonspecific influences, such as vigorous exercise, bacterial overgrowth of the
GI tract, shock, poor perfusion, B-vitamin deficiency, mitochondrial dysfunction or damage, and anemia,
among others. Tiglylglycine is a more specific indicator of mitochondrial dysfunction or damage. The
possibility of an inborn error of metabolism increases when the lactic acid value exceeds 300 mmol/
mol creatinine. There are many inborn errors of metabolism that are present with elevated lactic acid,
including disorders of sugar metabolism, pyruvate dehydrogenase deficiency, and mitochondrial
disorders.
Pyruvic Acid
Elevated by a number of non-specific factors, including vigorous exercise, bacterial overgrowth of
the GI tract, shock, poor perfusion, B-vitamin deficiency, mitochondrial dysfunction or damage, and
anemia, among others. High pyruvic acid indicates the possibility of an inborn error of metabolism
when the value exceeds 100 mmol/mol creatinine.
Clinical Significance of the Organic Acids Test
06/01/16
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77 Austin Street, PO Box 19033, Onekawa, Napier 4146
Ph 0800 439 633 | Fax 0800 439 630 | [email protected] | www.fxmed.co.nz
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The Great Plains Laboratory, Inc.
MITOCHONDRIAL MARKERS - KREBS CYCLE METABOLITES
Succinic Acid
Most commonly elevated due to a variety of metal and non-metal toxic chemical exposures. An
elevated result may indicate a relative deficiency of riboflavin and/or coenzyme Q10. Also produced
by bacterial degradation of unabsorbed glutamine supplement. Low levels may indicate the need for
leucine/isoleucine supplementation. Suggest supplementation with riboflavin and/or coenzyme Q10.
Fumaric Acid
Increased urinary fumaric acid may be due to impaired Krebs cycle function, a defect in the enzyme
fumarase, or in mitochondrial function. To support mitochondrial function, supplement with
coenzyme Q10, nicotinamide adenine dinucleotide (NAD+), L-carnitine and acetyl-L-carnitine,
riboflavin, nicotinamide, biotin, and vitamin E.
Malic Acid
Slightly elevated values usually indicate a higher need for nutrients such as niacin and coenzyme
Q10. When malic acid is simultaneously elevated with citric, fumaric, and 2-ketoglutaric acids, a
mitochondrial energy pathway dysfunction is strongly suggested.
2-Oxoglutaric Acid
Increased values in urine may be due to dietary vitamin deficiencies or the intake of 2-ketoglutaric acid
as a supplement. The conversion of 2-oxoglutaric acid to succinyl-CoA requires coenzyme A (derived
from pantothenic acid), flavin adenine dinucleotide (FAD) derived from riboflavin, and thiamine.
Aconitic Acid
Aconitase, the enzyme that metabolizes citric and aconitic acids, is dependent upon glutathione.
Elevated in mitochondrial disorders (e.g. Complex I and Pierson Syndrome). Elevated aconitic acid may
indicate an additional requirement for reduced glutathione.
Citric Acid
Elevations may be due to increased intake of citric acid-containing foods or result from intestinal
yeast-producing citric acid, or perhaps inhibiting the human citric acid cycle. Increased citric acid
may also indicate depletion of glutathione, which is required for the enzyme, aconitase to metabolize
both aconitic and citric acids. If pyroglutamic acid values are low, consider supplements containing
glutathione, or n-acetyl-cysteine.
MITOCHONDRIAL MARKERS - AMINO ACID METABOLITES
3-Methylglutaric Acid
3-Methylglutaconic
Significant increase is due to a reduced ability to metabolize the amino acid, leucine. This abnormality
is found in the genetic disease, methylglutaconic aciduria and in mitochondrial disorders.
3-Methylglutaconic acid may also be elevated. Supplementation with coenzyme Q10, niacin,
L-carnitine and acetyl-L-carnitine, riboflavin, nicotinamide, biotin, and vitamin E may be useful.
3-Hydroxyglutaric
Marker of glutaryl CoA dehydrogenase deficiency. This enzyme is involved in the breakdown of
lysine, hydroxylysine, and tryptophan, and is associated with the genetic disease, glutaric aciduria
type 1. Elevated 3-hydroxyglutaric acid may occur in combination with glutaric and glutaconic acids.
Symptoms of glutaryl CoA dehydrogenase deficiency are varied. Some individuals appear normal,
while others display encephalopathy, autism, cerebral palsy, and additional neurological abnormalities.
Treatment includes adherence to a diet low in lysine and supplementation with carnitine. Slight
elevations may indicate mitochondrial dysfunction.
NEUROTRANSMITTER METABOLISM
Phenylalanine and Tyrosine Metabolites
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HVA and VMA
HVA (homovanillic acid), a dopamine metabolite, and VMA (vanillylmandelic acid), a metabolite of
epinephrine and norepinephrine, are often elevated due to stress increasing catecholamine output
from the adrenal gland, or from lead toxicity. Elevated HVA may also result from the intake of L DOPA,
dopamine, phenylalanine, or tyrosine, or due to Clostridia metabolites.
HVA/VMA Ratio
An elevated ratio is often the result of a decreased conversion of dopamine to norepinephrine by the
enzyme, dopamine beta-hydroxylase. Inhibition of this enzyme is commonly caused by Clostridia byproducts, including HPHPA, 4-cresol, and 4-hydroxyphenylacetic acid.
Continued on the next page
Distributed in New Zealand by Functional & Integrative Medicine Ltd
77 Austin Street, PO Box 19033, Onekawa, Napier 4146
Ph 0800 439 633 | Fax 0800 439 630 | [email protected] | www.fxmed.co.nz
William Shaw, Ph.D., Director
|
11813 West 77th Street, Lenexa, KS 66214
|
(913) 341-8949
|
Fax (913) 341-6207
|
www.GPL4U.com
Tryptophan Metabolites
5-Hydroxyindoleacetic Acid
Metabolite of the neurotransmitter, serotonin. Elevated values may result from supplementing
tryptophan or 5 hydroxy tryptophan (5-HTP). Low values may indicate inadequate production of the
neurotransmitter, serotonin. Often slightly elevated by ingestion of foods high in serotonin, such as
avocado, banana, tomato, plum, walnut, pineapple, or eggplant. High values are found in carcinoid
syndrome.
Quinolinic Acid
Increased values in urine may be caused by various factors such as chronic inflammation from
microbial infections, central nervous system degeneration, excessive tryptophan supplementation,
or even exposure to phthalates. Reduce excess quinolinic acid by eliminating tryptophan
supplementation and also reduce exposure to infections and environmental pollutants. Brain damage
induced by quinolinic acid can be mitigated by supplements containing acetyl L-carnitine, melatonin,
B6, turmeric, and garlic.
Kynurenic Acid (KYNA)
The most common causes of elevated kynurenic acid are the use of tryptophan supplements and
the presence of chronic infections. Very high urine values are found in genetic disorders involving
kynureninase deficiency.
Quinolinic Acid / 5-HIAA Ratio
A high ratio indicates excessive inflammation due to recurrent infections, excessive tryptophan intake,
immune overstimulation, excessive adrenal production of cortisol, or excessive exposure to phthalates.
PYRIMIDINE METABOLITES - FOLATE METABOLISM
Uracil
Because folic acid is involved as a methyl donor in the conversion of uracil to thymine, elevated uracil may
indicate a defect in folic acid metabolism. Elevated uracil is found in about 10% of children with autism.
Thymine
Slightly elevated urinary thymine has no clinical significance. High values are associated with
inflammatory diseases and cancer. Elevated pyrimidines and elevated thymine have been reported in
dihydropyrimidine dehydrogenase deficiency, a rare genetic disease, which has been associated with
seizures and autism.
KETONE AND FATTY ACID OXIDATION
3-Hydroxybutyric Acid
Acetoacetic Acid
Ketones, such as 3-hydroxybutyric and acetoacetic acids, are the end-products of rapid or excessive
fatty acid breakdown. Common causes of elevated ketones are prolonged fasting, protein malnutrition,
high fat diet, vitamin B12 deficiency, severe GI Candida overgrowth, and pulmonary infections.
4-Hydroxybutyric Acid
A moderate urinary increase in 4-hydroxybutyric acid may be due to intake of dietary supplements
containing 4-hydroxybutyric acid, also known as gamma-hydroxybutyric acid. Very high levels may
indicate the genetic disorder involving succinic semialdehyde dehydrogenase deficiency.
Adipic Acid
Slightly elevated adipic acid may result from excessive ingestion of gelatin or other “junk” food
containing adipic acid as an additive. Elevated adipic acid may also indicate an abnormality in fatty
acid metabolism. Dietary supplements containing L-carnitine or L-acetyl-carnitine may be beneficial.
Suberic Acid
Sebacic Acid
Ethylmalonic Acid
Methylsuccinic Acid
Increased urinary products of the omega fatty acid metabolism pathway may be due to carnitine
deficiency, fasting, or increased intake of triglycerides from coconut oil, or some infant formulas. Very
elevated values may indicate a genetic disorder. Fatty acid oxidation defects are associated with
hypoglycemia and lethargy. Regardless of cause, intake of dietary supplements containing L-carnitine
or acetyl-L-carnitine may improve clinical symptoms.
Clinical Significance of the Organic Acids Test
06/01/16
Distributed in New Zealand by Functional & Integrative Medicine Ltd
77 Austin Street, PO Box 19033, Onekawa, Napier 4146
Ph 0800 439 633 | Fax 0800 439 630 | [email protected] | www.fxmed.co.nz
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The Great Plains Laboratory, Inc.
NUTRITIONAL MARKERS
Methylmalonic Acid
(Vitamin B12)
Slightly elevated methylmalonic acid is commonly associated with vitamin B12 deficiency, or other
factors such as pernicious anemia, GI bacterial metabolism, malabsorption, or gastroenteritis in very
young infants. Very elevated values may indicate a genetic disorder.
Pyridoxic Acid
(Vitamin B6)
A major metabolite of vitamin B6. High pyridoxic acid indicates high recent intake of vitamin B6.
Because some individuals may require very high doses of vitamin B6, high values do not necessarily
indicate the need to reduce vitamin B6 intake. Low values are associated with low B6 status, high
oxalates, and/or low neurotransmitters.
Pantothenic Acid
(Vitamin B5)
An essential vitamin (vitamin B5). High pantothenic acid indicates high recent intake of pantothenic
acid. Since some individuals may require very high doses of pantothenic acid, high values do not
necessarily indicate the need to reduce pantothenic acid intake.
Glutaric Acid
(Vitamin B2)
Elevation indicates riboflavin deficiency (vitamin B2), a common factor in moderate urinary increases
of glutaric acid. Other possible factors include fatty acid oxidation defects and metabolic effects of
valproic acid (Depakene), or celiac disease. The probability of a genetic disease is higher with very high
values. The use of dietary supplements containing riboflavin and coenzyme Q10 may improve clinical
symptoms. This compound may be elevated in about 10% of children with autism.
Ascorbic Acid
(Vitamin C)
Commonly elevated by supplementation. High values are usually of no concern, except in individuals
with extremely high intake (>2000 mg/day), in whom ascorbic acid may be converted to oxalic acid,
increasing the risk of kidney stones. It is unlikely that elevated vitamin C will contribute to kidney
stone formation if oxalic acid is in the normal range.
The precursor of coenzyme Q10 and cholesterol. Slightly increased values may be caused by
3-Hydroxy-3-methylglutaric Acid gastrointestinal yeast overgrowth. A moderate increase in urine HMG may also indicate decreased
(Coenzyme Q10)
synthesis of coenzyme Q10. Certain cholesterol-lowering drugs may inhibit the synthesis pathway and
result in high HMG values. Very elevated values may be caused by the genetic disorder, HMG aciduria.
N-Acetylcysteine Acid
A powerful antioxidant that increases the glutathione reserves in the body. Together with glutathione,
acetylcysteine directly binds to toxic metabolites. Although acetylcysteine may be beneficial under
certain conditions, excessive use of the supplement could be harmful.
Methylcitric Acid
(Biotin (Vitamin H)
Elevation usually indicates a biotin deficiency (Vitamin H). Biotin deficiency may be due to
malabsorption, excessive intake of raw egg white, dietary deficiency, or dysbiosis. Higher levels may
indicate the presence of genetic disorders involving biotin-dependent enzymes and may require biotin
supplementation at very high doses.
INDICATORS OF DETOXIFICATION
Glutathione
Pyroglutamic Acid
Pyroglutamic acid is a metabolite of glutathione. Glutathione serves as an antioxidant and is also
conjugated to toxic compounds in the liver. Elevated values are most commonly caused by glutathione
deficiency due to toxic exposure, such as acetaminophen toxicity. Elevated pyroglutamic acid may
also result from a genetic disorder, metabolic effects of certain antibiotics, or intake of certain infant
formulas. Supplementation with liposomal glutathione or N-acetyl-cysteine can raise glutathione
levels. Selenium is essential to the antioxidant activity of glutathione; usually, adequate selenium can
be obtained from a quality multivitamin.
2-Hydroxybutyric Acid
Elevated 2-hydroxybutyric acid is a byproduct of the breakdown of the sulfur amino acid metabolite,
cystathionine, which may be formed in excess during oxidative stress or when toxic exposures increase
the need for detoxification. When glutathione is depleted by excessive toxic exposure, pyroglutamic
acid may also be elevated. May also be elevated due to certain genetic SNPs in the methylation
pathway or deficiencies of methyl tetrahydrofolate, methyl B12, or betaine.
Continued on the next page
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Distributed in New Zealand by Functional & Integrative Medicine Ltd
77 Austin Street, PO Box 19033, Onekawa, Napier 4146
Ph 0800 439 633 | Fax 0800 439 630 | [email protected] | www.fxmed.co.nz
William Shaw, Ph.D., Director
|
11813 West 77th Street, Lenexa, KS 66214
|
(913) 341-8949
|
Fax (913) 341-6207
|
www.GPL4U.com
Ammonia Excess
Orotic Acid
Elevations are most commonly associated with ammonia toxicity. Elevated ammonia may result from
drug toxicity to the liver, viral liver infection, gastrointestinal bleeding, or inborn errors of ammonia
metabolism. Confirmation of a genetic disorder requires testing plasma amino acids.
Aspartame, Salicylates, or GI bacteria
2-Hydroxyhippuric Acid
A conjugate of the amino acids, glycine and hydroxybenzoic acid (salicylic acid). Intake of aspirin
(salicylates) or the growth of salicylate-producing gastrointestinal bacteria may elevate levels. Also
increased after the ingestion of the artificial sweetener, aspartame (Nutrasweet).
AMINO ACID METABOLITES
2-Hydroxyisovaleric Acid
2-Oxoisovaleric Acid
3-Methyl-2-oxovaleric Acid
2-Hydroxyisocaproic Acid
2-Oxoisocaproic Acid
A moderate increase of branched-chain amino acid metabolites in urine may result from lactic acidosis,
episodic ketosis, or deficiencies of the vitamins, thiamine or lipoic acid. Elevated 2-hydroxyisocaproic
acid in urine has also been linked to short bowel syndrome. A significant increase of branched-chain
amino acid metabolites is associated with the genetic disorders, maple syrup urine disease (MSUD)
and pyruvate dehydrogenase deficiency. Patients with slight to moderate elevations may use dietary
supplements containing thiamine to improve clinical symptoms.
2-Oxo-4-methiolbutyric Acid
Elevated in an inborn error of methionine metabolism. Confirmation of the genetic disorder requires
testing of plasma amino acids.
Mandelic Acid
Increased by dietary phenylalanine or phenylalanine supplementation, but also due to exposure
to styrene, a toxic environmental compound. Significant elevation is found in the genetic disorder,
phenylketonuria (PKU). A plasma phenylalanine test will rule out PKU.
Phenyllactic Acid
A metabolite of phenylalanine. Elevated values indicate increased intake of dietary phenylalanine or
the heterozygous carrier status (homozygosity) for the genetic disease, phenylketonuria (PKU). Values
observed in clinically diagnosed PKU typically exceed 200 mmol/mol creatinine.
Phenylpyruvic Acid
Moderate elevations may result from intake of phenylalanine, from genetic carrier status for PKU, or
from a deficiency in production of biopterin, a cofactor required for phenylalanine metabolism. Very
high values are associated with the genetic disease, PKU.
Homogentisic Acid
Homogentisic acid is elevated in the genetic disorder, homogentisic aciduria (alkaptonuria). Slight
increases may indicate the heterozygous genetic carrier state of the disease.
4-Hydroxyphenyllactic Acid
Increased values are commonly associated with tyrosinemias, which can result from immature
development of enzyme synthesis in infants or genetic deficiencies. Slight increases may be due to
increased tyrosine intake, bacterial gut metabolism, short bowel syndrome, or liver disease.
N-Acetylaspartic Acid
Elevated N-acetylaspartic acid is due to the genetic disorder, Carnavan’s disease, a potentially fatal
disease causing spongy degeneration of the brain.
Malonic Acid
Associated with the genetic disorders, malonyl-CoA decarboxylase deficiency and malonic aciduria
with normal malonyl-CoA decarboxylase activity. Slightly elevated values in urine are unlikely to be
clinically significant.
MINERAL METABOLITES
Phosphoric Acid
Phosphate urinary excretion is directly proportional to dietary intake. Processed foods high in
phosphate include: sodas, candy, ice cream, chocolate, mayonnaise, frozen pizza, commercially baked
goods, and meats. Excess phosphate is also associated with hyperparathyroidism, vitamin D-resistant
rickets, immobilization following paraplegia or fracture due to bone resorption, vitamin D intoxication,
blood lead levels above 1.5 ppm, renal tubular damage, familial hypophosphatemia, and metabolic
acidosis. Low urinary phosphate is most common in low phosphate intake and in vitamin D deficiency.
Clinical Significance of the Organic Acids Test
06/01/16
Distributed in New Zealand by Functional & Integrative Medicine Ltd
77 Austin Street, PO Box 19033, Onekawa, Napier 4146
Ph 0800 439 633 | Fax 0800 439 630 | [email protected] | www.fxmed.co.nz
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